Influenza is responsible for an estimated 36,000 deaths, 3.1 million hospitalization days, and 31 million outpatient visits per year in the US for a total economic burden of $90 million. It is remarkable that we know so much about the infectivity and pathogenicity of influenza viruses and so little about transmission and the inter-host dynamics of the virus in the environment. Many critical questions remain unanswered surrounding the dominant mode of transmission, seasonality, and factors that enable a certain strain to go airborne. We hypothesize that pathogen-environment interactions may play a key role in the transmissibility of the virus. Specifically, evaporation-induced changes in the chemica composition of aerosols, such as lowered pH, increased salt and protein concentrations, crystallization, and/or phase separations, affect the structure and/or function of the virus. The overall goal of the project is to elucidate the mechanisms by which humidity affects influenza virus transmissibility. Our specific objectives are (1) to determine the relationship between virus viability and solute concentrations in droplets/aerosols, (2) to characterize respiratory droplet/aerosol composition in terms of solute concentrations, pH, crystallization, and phase separation as a function of relative humidity (RH), (3) to pinpoint the location of viruses within droplets/aerosols, (4) to identify the mechanism(s) by which the virus is inactivated in droplets/aerosols, and (5) to confirm findings by exposing aerosolized viruses at known concentrations to a guinea pig model under various RH. This research is innovative for five significant reasons. First, it aims to redefine the current paradigm used to describe airborne transmission of diseases, which relies on outdated terminology and concepts that have been eclipsed by major advances in aerosol science. Second, this research introduces pathogen- environment interactions as playing a significant role in the transmission of infectious diseases. Third, we have developed an innovative hypothesis that addresses a question that has stymied researchers for decades: How can humidity affect a virus that is encased in an aerosol? The fourth innovative aspect of this research is the use of an interdisciplinary approach, which is essential to making a large leap in understanding airborne transmission of infectious disease. The topic draws upon engineering, virology, and chemistry. Fifth, our innovative technical approach brings modern aerosol, biological, and nanoscience methods to the problem. Results of this research have the potential to promote major advances in predicting the pandemic potential of influenza virus strains, forecasting of disease dynamics, and development of infection control strategies.